Drug delivery system for averting pharmacokinetic drug interaction and method thereof

ABSTRACT

The present invention is a system for averting undesirable pharmacokinetic drug interaction between a drug and concomitant drug(s), which consists of controlling the in vivo release time and/or release site of the drug and/or the concomitant drug.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationNo. 60/197,574, filed Apr. 17, 2000, the teaching of which is herebyincorporated by reference in its entirety for all purposes.

TECHNICAL FIELD

The present invention pertains to a novel means for averting undesirablepharmacokinetic (drug) interaction between a drug and concomitantdrug(s) (e.g., between a drug and a food) in vivo in humans, and uses asthe means of aversion a drug delivery system with which the in vivorelease time and/or the release site of the drug is controlled.

BACKGROUND OF THE INVENTION

Recently, drugs are rarely used singularly as a result ofdiversification of medicine and changes in patient phase with aging, andin many cases multiple drugs are administered simultaneously or atstaggered administration times. In this case, interaction between drugsthat are administered concomitantly sometimes occurs. Interactionbetween the drugs in question is classified as pharmacodynamic druginteraction, whereby there is a change in sensitivity, etc., to the drugat its site of action, and pharmacokinetic drug interaction, where thereis a change in the in vivo kinetics of the drug. With respect to theformer, interaction by concomitant use can be estimated if the clinicalmode of action of the drugs is known, and the fact of the matter is thatthe actual results of concomitant therapy are improved using this sameinteraction. However, with respect to the latter, clinically, the invivo kinetics of a drug is still unknown and even when it is known,unexpected results occur when drugs are combined (“ClinicalPharmacokinetics, Revised Version 2,” Chapter VII: Drug Interaction,page 107, Ryuichi Kato, author, Nankodo Publishing).

Pharmacokinetic drug interaction almost always develops because thedrugs themselves compete for one route (enzymes, carriers, etc.) whendrugs that use the same routes in terms of drugs absorption,distribution, metabolism or excretion are used concomitantly.

This type of pharmacokinetic drug interaction is undesirable unless itis used for an additive action or synergism. The method has been adoptedfor averting concomitant use of drugs that interact with one anotherwhen a prescription is written by a physician or pharmacist wherebyattention is drawn to “Drug Safety Data” presented by the Ministry ofHealth and Welfare and the column on precautions for concomitant usecontained in the attached drug literature.

Moreover, the claim is presented in “Yakuzai Yosokugaku Nyumon,”(Yasufumi Sawada, author; Yakugyo Jiho Publishers) that it is possibleto avert interaction with an administration protocol whereby theadministration time of concomitant drugs to a patient is staggered.However, the administration time is precisely specified and the protocolcalls for administration of as much as 6 to 7 times/day with concomitantuse of metal cation-containing antacids (magnesium, aluminum, etc.) andnew quinolones (norfloxacin, etc.), which were used as examples in thistext, and in view of patient compliance, this protocol cannotrealistically be used.

Consequently, even if from a pharmacological standpoint the drugsthemselves realize excellent therapeutic results when usedconcomitantly, concomitant use has been averted in the past because ofdrug interaction and satisfactory therapeutic results could not berealized.

Moreover, since pharmacokinetic interaction with drugs is induced bysome foods, pharmacists give instructions on how to take drugsexplaining precautions when drugs are taken. However, this has become asource of reduced patient compliance.

SUMMARY OF THE INVENTION

In certain embodiments, the present invention provides a system foraverting undesirable pharmacokinetic drug interaction between a drug andconcomitant drug(s), the system comprising controlling the in vivorelease time and/or release site of the drug and/or the concomitantdrug(s).

In another embodiment, the present invention provides a method or use ofa drug delivery system which consists of controlling the in vivo releasetime and/or release site a drug and/or concomitant drug(s), for avertingundesirable pharmacokinetic drug interaction between the drug and theconcomitant drug(s).

In another embodiment, the present invention provides a method or use ofa drug delivery system which consists of controlling the in vivo releasetime and/or release site of the drug and/or concomitant drug(s), foraverting undesirable drug interaction between the drug and theconcomitant drug(s), both of which use the same route in terms of invivo drug absorption, distribution, metabolism or excretion in humans.

In another embodiment, the present invention provides a method or use ofa drug delivery system which consists of timed-release control of a drugor control of the site of release of a drug to the digestive tract, foraverting undesirable drug interaction between the said drug andconcomitant drug(s), both of which are metabolized by the same molecularspecies of drug-metabolizing enzyme in humans, or between the said drugand concomitant drug(s) that is metabolized by the molecular species ofdrug-metabolizing enzymes that is inhibited by the said drug.

In another embodiment, the present invention provides a method or use ofa drug delivery system which consists of timed-release control of a drugor control of release of a drug specifically to the lower digestivetract, for averting undesirable drug interaction between the said drugand concomitant drug(s), both of which metabolized by the drugmetabolizing enzyme CYP3A4, or between the said drug that inhibit CYP3A4and concomitant drug(s) that is metabolized by CYP3A4.

In another embodiment, the present invention provides a method ofaverting undesirable pharmacokinetic drug interaction between a drug andconcomitant drug(s), by using a drug delivery system with which the invivo release time and/or release site of the drug and/or the concomitantdrug(s) is controlled.

In another embodiment, the present invention provides a method foraverting undesirable drug interaction between a drug and concomitantdrug(s), both of which use the same route in terms of in vivo drugabsorption, distribution, metabolism or excretion in humans, by using adrug delivery system with which the in vivo release time and/or releasesite of the drug and/or the concomitant drug(s) is controlled.

In another embodiment, the present invention provides a method foraverting undesirable drug interaction between a drug and concomitantdrug(s), both of which are metabolized by the same molecular species ofdrug-metabolizing enzyme in humans or between a drug and concomitantdrug(s) that is metabolized by the molecular species of drugmetabolizing-enzymes that is inhibited by the said drug, by using a drugdelivery system with which there is timed-release control of the saiddrug or control of the site of release of the said drug to the digestivetract.

In another embodiment, the present invention provides a method foraverting undesirable drug interaction between a drug and concomitantdrug(s), both of which metabolized by the drug metabolizing enzymeCYP3A4 or between a drug that inhibit CYP3A4 and concomitant drug thatis metabolized by CYP3A4, by using a drug delivery system with whichthere is timed-release control of the said drug or control of release ofthe said drug specifically to the lower digestive tract.

In still another embodiment, the present invention provides a method oruse of a drug preparation which consists of controlling the in vivorelease time and/or release site of a drug, for averting undesirablepharmacokinetic drug interaction between the said drug and concomitantdrug(s).

In still another embodiment, the present invention provides a method oruse of a drug preparation which consists of controlling the in vivorelease time and/or release site of a drug, for averting undesirabledrug interaction between the said drug and concomitant drug(s), both ofwhich use the same route in terms of in vivo drug absorption,distribution, metabolism or excretion in humans.

In another embodiment, the present invention provides a method or use ofa drug preparation which consists of timed-release control of a drug orcontrol of the site of release of a drug to the digestive tract iscontrollable, for averting undesirable drug interaction on the in vivokinetics of concomitant drug(s) by the said drug that inhibits the invivo metabolism of the concomitant drug(s) by drug-metabolizing enzymesin humans.

In another embodiment, the present invention provides a method or use ofa drug preparation which consists of timed-release control of a drug orcontrol of release of a drug specifically to the lower digestive tract,for averting undesirable effects on the blood concentration ofconcomitant drug(s) by the said drug that inhibits the in vivometabolism of the concomitant drug(s) by CYP3A4 in humans. Preferably,the drug and the concomitant drug are a combination selected fromanfentanyl, fentanyl, sulfentanyl, cocaine, dihydrocodeine, oxycodeine,tramadol, erythromycin, clarithromycin, troleandomycin, azithromycin,itraconazole, ketoconazole, dapsone, midazolam, triazolam, alprazolam,diazepam, zolpidem, felodipine, nifedipine, nitrendipine, amlodipine,isradipine, nicardipine, nimodipine, nisoldipine, nildipine, bepridil,diltiazem, verapamil, astemizole, terfenadine, loratidine, cyclosporine,tacrolimus, rapamycin, amiodarone, disopyramide, lidocaine, propafenone,quinidine, imipramine, amitriptyline, clomipramine, nafazodone,sertraline, trazodone, haloperidol, pimozide, carbamazepine,ethosuximide, trimethadione, simvastatin, lovastatin, fluvastatin,atrovastatin, etoposide, ifosfamide, paclitaxel, tamoxifen, taxol,vinblastine, vincristine, indinavir, ritonavir, saquinavir,testosterone, prednisolone, methylprednisolone, dexamethasone,proguanil, warfarin, finasteride, flutamide, ondansteron, zatsetrone,cisapride, cortisol, zonisamide, desmethyldiazepam, and conivaptan.

In still yet another embodiment, the present invention provides a methodor use of a drug delivery system which consists of controlling the invivo release time and/or release site a drug, for averting undesirablepharmacokinetic interaction between the drug and food(s).

In still yet another embodiment, the present invention provides a methodfor averting undesirable pharmacokinetic interaction between a drug andfood(s), by using a drug delivery system whereby the in vivo releasetime and/or release site of the drug is controlled.

These and other embodiments will become more apparent when read with thedetailed description and drawings, which follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the results of dissolution tests of conivaptantimed-release preparation.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The inventors focused on the use of a drug delivery system for avertingundesirable drug interaction, particularly pharmacokinetic druginteraction, and were successful at materialization of the same. Theydiscovered that with respect to drug interaction that is produced as aresult of the drugs themselves competing for one route (enzyme, carrier,etc.) when multiple drugs that use the same route in terms of drugabsorption, distribution, metabolism or excretion are administeredconcomitantly, drug interaction at the route that is the problem can beaverted by controlling the drug release time and/or release site with adrug delivery system. Furthermore, not only drug interaction betweenmultiple drugs, but also interaction between drugs and foods, can besimilarly averted.

Aversion of drug interaction as a purpose and use of the technology inquestion has not been specifically discussed in the technical field ofdrug delivery systems.

That is, the present invention pertains to a system for avertingundesirable pharmacokinetic drug interaction between a drug andconcomitant drug(s), which consists of controlling the in vivo releasetime and/or release site of the drug and/or the concomitant drug(s). Inparticular, the present invention pertains to a system for avertingundesirable drug interaction between a drug and concomitant drug(s),both of which use the same route in terms of in vivo drug absorption,distribution, metabolism or excretion in humans, which consists ofcontrolling the in vivo release time and/or release site of the drugand/or the concomitant drug(s). The present invention is preferably asystem for averting undesirable drug interaction between a drug andconcomitant drug(s), both of which are metabolized by the same molecularspecies of drug-metabolizing enzyme in humans or between a drug andconcomitant drug(s) that is metabolized by the molecular species ofdrug-metabolizing enzymes that is inhibited by the said drug, whichconsists of timed-release control of the said drug or control of thesite of release of the said drug to the digestive tract. It is furtherpreferred that the present invention is a system for avertingundesirable drug interaction between a drug and concomitant drug(s),both of which metabolized by the drug metabolizing enzyme CYP3A4, orbetween a drug that inhibits CYP3A4 and concomitant drug(s) that ismetabolized by CYP3A4, which consists of timed-release control of thesaid drug or controlling release specifically in the lower digestivetract of the said drug.

Moreover, the present invention pertains to the use of a drug deliverysystem which consists of controlling the in vivo release time and/orrelease site a drug and/or concomitant drug(s), for averting undesirablepharmacokinetic drug interaction between the drug and the concomitantdrug(s). In particular, the present invention pertains to the use of adrug delivery system which consists of controlling the in vivo releasetime and/or release site of the drug and/or concomitant drug(s), foraverting undesirable drug interaction between the drug and theconcomitant drug(s), both of which use the same route in terms of invivo drug absorption, distribution, metabolism or excretion in humans.The present invention preferably is the use of a drug delivery systemwhich consists of timed-release control of a drug or control of the siteof release of a drug to the digestive tract, for averting undesirabledrug interaction between the said drug and concomitant drug(s), both ofwhich are metabolized by the same molecular species of drug-metabolizingenzyme in humans, or between the said drug and concomitant drug(s) thatis metabolized by the molecular species of drug-metabolizing enzymesthat is inhibited by the said drug. It is further preferred that thepresent invention is the use of a drug delivery system which consists oftimed-release control of a drug or control of release of a drugspecifically to the lower digestive tract, for averting undesirable druginteraction between the said drug and concomitant drug(s), both of whichmetabolized by the drug metabolizing enzyme CYP3A4, or between the saiddrug that inhibit CYP3A4 and concomitant drug(s) that is metabolized byCYP3A4.

Moreover, the present invention pertains to a method for avertingundesirable pharmacokinetic drug interaction between a drug andconcomitant drug(s), by using a drug delivery system whereby the in vivorelease time and/or release site of the drug and/or the concomitantdrug(s) is controlled. In particular, the present invention pertains toa method for averting undesirable drug interaction between a drug andconcomitant drug(s), both of which use the same route in terms of invivo drug absorption, distribution, metabolism or excretion in humans,by using a drug delivery system with which the in vivo release timeand/or release site of the drug and/or the concomitant drug(s) iscontrolled. The present invention is preferably a method for avertingundesirable drug interaction between a drug and concomitant drug(s),both of which are metabolized by the same molecular species ofdrug-metabolizing enzyme in humans or between a drug and concomitantdrug(s) that is metabolized by the molecular species of drugmetabolizing-enzymes that is inhibited by the said drug, by using a drugdelivery system with which there is timed-release control of the saiddrug or control of the site of release of the said drug to the digestivetract. It is further preferred that the present invention is a methodfor averting undesirable drug interaction between a drug and concomitantdrug(s), both of which metabolized by the drug metabolizing enzymeCYP3A4 or between a drug that inhibits CYP3A4 and concomitant drug(s)that is metabolized by CYP3A4, by using a drug delivery system withwhich there is timed-release control of the said drug or control ofrelease of the said drug specifically to the lower digestive tract.

The present invention further pertains to a drug preparation foraverting undesirable pharmacokinetic drug interaction between a drug andconcomitant drug(s), which consists of controlling the in vivo releasetime and/or release site of the said drug. In particular, the presentinvention pertains to a drug preparation for averting undesirable druginteraction between a drug and concomitant drug(s), both of which usethe same route in terms of in vivo drug absorption, distribution,metabolism or excretion in humans, which consists of controlling the invivo release time and/or release site of the said drug. The presentinvention is preferably a drug preparation for averting undesirable druginteraction on the in vivo kinetics of a drug by concomitant drug(s)that inhibits in vivo metabolism of the said drug in humans, whichconsists of timed-release control of the concomitant drug(s) or controlof the site of release of the concomitant drug(s) to the digestivetract. It is further preferred that the present invention is a drugpreparation for averting undesirable effects on the blood concentrationof a drug by concomitant drug(s) that inhibits the in vivo metabolism ofthe said drug by CYP3A4 in humans, which consists of timed releasecontrol of the said drug or controlling release specifically in thelower digestive tract of the concomitant drug(s).

Moreover, the present invention pertains to the use of a drugpreparation which consists of controlling the in vivo release timeand/or release site of a drug, for averting undesirable pharmacokineticdrug interaction between the said drug and concomitant drug(s). In otherwords, the present invention pertains to a drug preparation whichconsists of controlling the in vivo release time and/or release site ofa drug, for averting undesirable drug interaction between the said drugand concomitant drug(s), both of which use the same route in terms of invivo drug absorption, distribution, metabolism or excretion in humans.The present invention is preferably the use of a drug preparation whichconsists of timed-release control of a drug or control of the site ofrelease of a drug to the digestive tract, for averting undesirable druginteraction on the in vivo kinetics of concomitant drug(s) by the saiddrug that inhibits the in vivo metabolism of the concomitant drug(s) bydrug-metabolizing enzymes in humans. It is further preferred that thepresent invention is the use of a drug preparation which consists oftimed-release control of a drug or control of release of a drugspecifically to the lower digestive tract, for averting undesirableeffects on the blood concentration of concomitant drug(s) by the saiddrug that inhibits the in vivo metabolism of the concomitant drug(s) byCYP3A4 in humans.

Furthermore, the present invention pertains to a method for avertingundesirable pharmacokinetic drug interaction between a drug andconcomitant drug(s), which comprises administering to patients a drugpreparation with which the in vivo release time and/or release site ofthe said drug is controlled. In particular, the present inventionpertains to a method for averting undesirable drug-interaction between adrug and concomitant drug(s), both of which use the same route in termsof in vivo drug absorption, distribution, metabolism or excretion inhumans, which comprises administering to patients a drug preparationwith which the in vivo release time and/or release site of the said drugis controllable. The present invention is preferably a method foraverting undesirable drug-interaction on the in vivo kinetics of a drugby a concomitant drug that inhibits the in vivo metabolism of the saiddrug by drug-metabolizing enzymes in humans, which comprisesadministering to patients a drug preparation with which timed-release ofthe concomitant drug or release site of the concomitant drug to thedigestive tract is controllable. It is further preferred that thepresent invention is a method for averting undesirable effects on theblood concentration of a drug by a concomitant drug that inhibits the invivo metabolism of the said drug by CYP3A4, which comprisesadministering to patients a drug preparation with which timed-release ofthe concomitant drug or release of the concomitant drug specifically tothe lower digestive tract is controllable.

Moreover, the present invention pertains to a system for avertingundesirable pharmacokinetic interaction between a drug and food(s),which consists of controlling the in vivo release time and/or releasesite of the drug. In particular, the present invention pertains to asystem for averting undesirable pharmacokinetic interaction between adrug and food(s), both of which use the same route in terms of in vivodrug absorption, distribution, metabolism or excretion in humans, whichconsists of controlling the in vivo release time and/or release site ofthe drug. The present invention is preferably a system for avertingundesirable pharmacokinetic interaction between a drug and food(s), bothof which are metabolized by the same molecular species ofdrug-metabolizing enzyme in humans, or between a drug and food(s) thatinhibit the molecular species of drug metabolizing enzymes thatmetabolize the said drug, which consists of timed-release control of thesaid drug or control of the site of release of the said drug to thedigestive tract. It is further preferred that the present invention is asystem for averting undesirable pharmacokinetic interaction between adrug and food(s), both of which metabolized by the drug-metabolizingenzyme CYP3A4, or between a drug that is metabolized by CYP3A4 andfood(s) that inhibit CYP3A4, which consists of timed release control orcontrolling release specifically in the lower digestive tract of thesaid drug.

In addition, the present invention pertains to the use of a drugdelivery system which consists of controlling the in vivo release timeand/or release site of a drug, for averting undesirable pharmacokineticinteraction between the drug and food(s). In particular, the presentinvention pertains to the use of a drug delivery system which consistsof controlling the in vivo release time and/or release site of a drug,for averting undesirable pharmacokinetic interaction between the drugand food(s), both of which use the same route in terms of in vivo drugabsorption, distribution, metabolism or excretion in humans. The presentinvention preferably is the use of a drug delivery system which consistsof timed-release control of a drug or control of the site of release ofa drug to the digestive tract, for averting undesirable pharmacokineticinteraction between the drug and food(s), both of which are metabolizedby the same molecular species of drug metabolizing enzyme in humans orbetween the drug and food(s) that inhibits the molecular species ofdrug-metabolizing enzymes that metabolize the said drug. It is furtherpreferred that the present invention is the use of a drug deliverysystem which consists of timed-release control of a drug or control ofrelease of a drug specifically to the lower digestive tract, foraverting undesirable pharmacokinetic interaction between the drug andfood(s), both of which metabolized by the drug metabolizing enzymeCYP3A4, or between the drug that are metabolized by CYP3A4 and food(s)that inhibits CYP3A4.

Furthermore, the present invention pertains to a method for avertingundesirable pharmacokinetic interaction between a drug and food(s), byusing a drug delivery system whereby the in vivo release time and/orrelease site of the drug is controlled. In particular, the presentinvention pertains to a method for averting undesirable pharmacokineticinteraction between a drug and food(s), both of which use the same routein terms of in vivo drug absorption, distribution, metabolism orexcretion in humans by using a drug delivery system with which the invivo release time and/or release site of drugs is controlled. Thepresent invention is preferably a method for averting undesirablepharmacokinetic interaction between a drug and food(s), both of whichare metabolized by the same molecular species of drug-metabolizingenzyme in humans or between a drug and food(s) that inhibits themolecular species of drug metabolizing enzymes that metabolize the saiddrug, by using a drug delivery system with which there is timed-releasecontrol of the drug or control of the site of release of the drug to thedigestive tract. It is further preferred that the present invention is amethod for averting undesirable pharmacokinetic interaction between adrug and food(s), both of which metabolized by the drug-metabolizingenzyme CYP3A4 or between a drug that are metabolized by CYP3A4 andfood(s) that inhibits CYP3A4, by using a drug delivery system with whichthere is timed-release control of the drug or control of release of thedrug specifically to the lower digestive tract.

Furthermore, the present invention pertains to a drug preparation foraverting undesirable pharmacokinetic interaction between a drug andfood(s), which consists of controlling the in vivo release time and/orrelease site of the drug. In particular, the present invention pertainsto a drug preparation for averting undesirable pharmacokineticinteraction between a drug and food(s), both of which use the same routein terms of in vivo drug absorption, distribution, metabolism orexcretion in humans, which consists of controlling the in vivo releasetime and/or release site of the drug. The present invention ispreferably a drug preparation for averting undesirable pharmacokineticinteraction on the in vivo kinetics of a drug by food(s) that inhibitsin vivo metabolism of the drug in humans, which consists oftimed-release control of the drug or control of the site of release ofthe drug to the digestive tract. It is further preferred that thepresent invention is a drug preparation for averting undesirable effectson the blood concentration of a drug by food(s) that inhibits the invivo metabolism of the drug by CYP3A4 in humans, which consists oftimed-release control of the drug or controlling release specifically tothe lower digestive tract of the drug.

Moreover, the present invention pertains to the use of a drugpreparation which consists of controlling the in vivo release timeand/or release site of a drug, for averting undesirable pharmacokineticinteraction between the drug and food(s). In other words, the presentinvention pertains to the use of a drug preparation which consists ofcontrolling the in vivo release time and/or release site of a drug, foraverting undesirable pharmacokinetic interaction between a drug andfood(s), both of which use the same route in terms of in vivo drugabsorption, distribution, metabolism or excretion in humans. The presentinvention is preferably the use of a drug preparation which consists oftimed-release control of a drug or control of the site of release of adrug to the digestive tract, for averting undesirable pharmacokineticinteraction on the in vivo kinetics of the drug by food(s) that inhibitthe in vivo metabolism in humans of the drug by drug-metabolizingenzymes. It is further preferred that the present invention is the useof a drug preparation which consists of timed-release control of a drugor control of release of a drug specifically to the lower digestivetract, for averting undesirable effects on the blood concentration ofthe drug by food(s) that inhibits in vivo metabolism of the drug byCYP3A4 in humans.

Furthermore, the present invention pertains to a method for avertingundesirable pharmacokinetic interaction between a drug and food(s),which comprises administering to patients a drug preparation with whichthe in vivo release time and/or release site of the drug is controlled.In particular, the present invention pertains to a method for avertingundesirable pharmacokinetic interaction between a drug and food(s), bothof which use the same route in terms of in vivo drug absorption,distribution, metabolism or excretion in humans, which comprisesadministering to patients a drug preparation with which the in vivorelease time and/or release site of the drug is controllable. Thepresent invention is preferably a method for averting undesirableinteraction on the in vivo kinetics of a drug by food(s) that inhibitsthe in vivo metabolism of the drug by drug-metabolizing enzymes inhumans, which comprises administering to patients a drug preparationwith which timed-release of the drug or release site of the drug to thedigestive tract is controllable. It is further preferred that thepresent invention is a method for averting undesirable effects on theblood concentration of a drug by food(s) that inhibits in vivometabolism of the drug by CYP3A4, which comprises administering topatients a drug preparation with which timed-release of the drug orrelease of the drug specifically to the lower digestive tract iscontrollable.

The present invention will now be explained in further detail.

In the present invention the term drug interaction means pharmacokineticdrug interaction, in other words, drug interaction between multipledrugs that use the same route in terms of (a)drug metabolism, (b)drugabsorption, (c)drug distribution, or (d)drug excretion. Specificinteraction is discussed below:

(a) Interaction in Terms of Drug Metabolism

Drugs are deactivated or converted to water-soluble metabolites that arereadily excreted via the kidneys by the effects of drug-metabolizingenzymes in the liver. Cytochrome P450 (CYP) is said to be the mostimportant drug-metabolizing enzyme. It is said that approximately 70% ofpharmacokinetic drug interaction is around drug metabolism, and of this,95% or more is interaction via CYP. Many molecular species of CYP exist,and those that play the most important role in drug metabolism areCYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. The molecular species of CYPinvolved in drug metabolism is determined by the chemical structure ofthe drug. Moreover, the molecular species of CYP involved in metabolismvaries with each site in the chemical structure, and there are alsodrugs that are metabolized by multiple molecular species of CYP.

When multiple drugs metabolized by the same molecular species of CYPcompete for these metabolizing enzymes, the extent of competition varieswith the affinity of the drug for the CYP, but it appears thatmetabolism is inhibited in some way. This results in drug interaction,such as an elevated blood concentrations, prolonged blood half-life,etc. Moreover, there are of course also drugs that are not metabolized,but have an inhibiting effect on specific molecular species of CYP.

Theophylline, caffeine, phenacetin, clomipramine, imipramine,fluvoxamine, zolpidem, clozapine, propranolol, propafenone,chlorzoxazone, tacrine, acetaminophen, ondansterone, verapamil, etc.,are drugs that are metabolized by CYP1A2 and drugs that inhibit CYP1A2.

Diclofenac, naproxen, ibuprofen, piroxicam, flurbiprofen, indomethacin,phenytoin, carbamazepin, tolbutamide, glibenclamide, glipizide,glimepiride, warfarin, losartan, torsemide, dronabinol, tenoxicam,mefanamic acid, sulfafenazole, etc., are drugs that are metabolized byCYP2C9 and drugs that inhibit CYP2C9.

Mephenytoin, diazepam, phenytoin, phenobarbital, hexobarbital,mephobarbital, omeprazole, lansoprazole, proguanil, amitriptyline,clomipramine, imipramine, sitalopram, propranolol, thiridazine,carisoprodol, warfarin, nirvanol, etc., are drugs metabolized by CYP2C19and drugs that inhibit CYP2C19.

Propafenone, flekainid, mexiletine, enkainid, spartein,N-propylazimalin, metoprolol, timolol, pindolol, propranolol, bufuralol,perbutolol, popindolol, alprenolol, carbedilol, debrisokin, indolamine,guanoxan, urapidil, nisergolin, risperidone, thioridazine, perphenazine,clozapine, trifluperiol, fluphenazine, chlorpromazine, haloperidol,clomipramine, nortriptyline, amitriptyline, imipramine, trimipramine,desipramine, zolpidem, brofalomin, amiframine, paroxetine, fluoxetine,maprotiline, banrafaxin, fluvoxamin, trazadone, tomoxetin,dihydrocodeine, oxycodeine, codeine, tramadol, dextromethorphan,femformine, perhexelin, chlomiopran, quinidine, cimetidine, ondansteron,etc., are drugs that are metabolized by CYP2D6 and drugs that inhibitCYP2D6.

Anfentanyl, fentanyl, sulfentanyl, cocaine, dihydrocodeine, oxycodeine,tramadol, erythromycin, clarithromycin, troleandomycin, azithromycin,itraconazole, ketoconazole, dapsone, midazolam, triazolam, alprazolam,diazepam, zolpidem, felodipine, nifedipine, nitrendipine, amlodipine,isradipine, nicardipine, nimodipine, nisoldipine, nildipine, bepridil,diltiazem, verapamil, astemizole, terfenadine, loratidine, cyclosporine,tacrolimus, rapamycin, amiodarone, disopyramide, lidocaine, propafenone,quinidine, imipramine, amitriptyline, clomipramine, nafazodone,sertraline, trazodone, haloperidol, pimozide, carbamazepine,ethosuximide, trimethadione, simvastatin, lovastatin, fluvastatin,atrovastatin, etoposide, ifosfamide, paclitaxel, tamoxifen, taxol,vinblastine, vincristine, indinavir, ritonavir, saquinavir,testosterone, prednisolone, methylprednisolone, dexamethasone, proguanilwarfarin, finasteride, flutamide, ondansteron zatosetron, cisapride,cortisol, zonisamide, desmethyldiazepam, conivaptan, etc., are drugsthat are metabolized by CYP3A4 and drugs that inhibit CYP3A4 (SogoRinsho, 48(6), 1427-1431, 1999/Seishinka Chiryogaku, 14(9), 951-960,1999).

Inhibition of metabolism resulting in elevation of blood concentrationof midazolam and terfenadine, cyclosporine, etc., by erythromycin,methyl prednisolone by ketoconazole, and lovastatin by itraconazole areexamples of drugs metabolized by CYP3A4 whose metabolism is inhibited byconcomitant use.

Moreover, there are cases where foods that are metabolized by the samespecies of CYP as drugs compete for the same metabolizing enzymes toinhibit in some way the metabolism of these drugs. Moreover, there arealso foods that inhibit a specific molecular species of CYP. Forinstance, various components contained in grapefruit juice inhibitCYP3A4 and therefore, interaction resulting in elevated bloodconcentrations of the drugs is seen when cyclosporine and tacrolimus,midazolam, triazolam, terfenadine, etc., which are metabolized byCYP3A4, are taken with grapefruit juice.

On the other hand, it is known that there are drugs that inducedrug-metabolizing enzymes. For instance, rifampicin induces CYP3A4,CYP2C9 and CYP2C19 to promote metabolism of nifedipine, warfarin,diazepam, cyclosporine, disopyramide, torbutamide, ethinyl estradiol,etc., and reduce blood concentrations.

(b) Interaction in Terms of Drug Absorption

The route of absorption of drugs is also by the skin or oral mucosa,etc., but the main route of absorption is by the digestive tract.

Changes in gastric pH due to the effect of other drugs usedconcomitantly changes solubility of drugs and controls or promotesabsorption from the digestive tract. For instance, gastric pH rises to 3to 5 with administration of cimetidine during concomitant use ofcimetidine and ketoconazole and as a result, there is a reduction insolubility of ketoconazaole and absorption via the digestive tract isinhibited, leading to a reduction in the blood concentration.

There are cases where when a drug is actively absorbed with concomitantdrugs via the same carriers on the epithelial cells of the smallintestines, absorption of the concomitant drugs is inhibited by thisdrug. For instance, it is reported that there is a reduction byapproximately half in the cefadroxil plasma concentration whencefadroxil, a betalactam antibiotic, is concomitantly administered withcefalexine. This reduction in the blood concentration is apparently dueto inhibition as a result of competition for the carrier by the twodrugs.

(c) Interaction in Terms of Drug Distribution

Drugs that have been absorbed via the digestive tract or have moved tothe blood from the site of administration are distributed to blood cellsat a specific ratio, or bind with proteins in plasma. The free fractionof the drug is distributed to each tissue to realize pharmacologicalaction and therefore, when drug bound to protein is expelled from thisbinding site and interaction occurs so that the concentration of thefree fraction of the drug rises, this pharmacological effect isenhanced. For instance, warfarin, torbutamide, etc., are released fromthe protein binding site, resulting in a rise in the concentration ofthe free fraction of the drug, when they are concomitantly used withaspirin, etc.

Moreover, P glycoproteins are found in the cells of the mucosa of thesmall intestines, cells of the uriniferous tubules, and endothelialcells of the capillaries of the brain, and they have the mechanism oftransporting many drugs to outside the cells. When a drug that inhibitsP glycoprotein is concomitantly used with a drug that is transported viaP glycoprotein, there are cases where secretion of drugs into theintestines, transporting drugs out of the brain, and excretion in urineare inhibited. Vinblastin, vincristin, doxorubicin, etoposide, taxol,adriamycin, dexamethasone, hydrocortisone, verapamil, diltiazem,nifedipine, nicardipine, cyclosprin, tacrolimus, acebutolol, metoprolol,nadolol, timolol, prostaglandin, rodamine 123, digoxin, colchicine,dideoxyforscolin, etc., are drugs that are transported out by Pglycoproteins. Etoposide, hydrocortisone, progesterone, testosterone,verapamil, diltiazem, nifedipine, felodipine, nitrendipine, nicardipine,cyclosporine, tacrolimus, amiodarone, lidocaine, quinidine,itraconazole, ketoconazole, erythromycin, tamoxifen, terfenadine,clorpromazine, selprolol, diprofloxacine, spironolactone are drugs thatinhibit P glycoproteins (“Clinical Pharmacokinetics, Revised Version 2,”Chapter II. Absorption of drugs from site of administration, page 19,Ryuichi Kato, author, Nankodo Publishers).

(d) Interaction in Terms of Excretion of Drugs.

Drugs that have entered the body are excreted into the urine by thekidneys and are secreted and re-absorbed in the uriniferous tubules.Anionic carriers and cationic carriers participate in secretion from theuriniferous tubules. There is a possibility that drugs that use the samecarrier will interact with one another. Probenecid, diodrast,acetazolamide, etc., are drugs that inhibit secretion via anioniccarriers. Quinine, methyl nicotinamide, trazolin, tetramethyl ammonium,etc., are drugs that inhibit secretion via cationic carriers.

On the other hand, when re-absorption from the uriniferous tubules isinhibited, there is an increase in the amount excreted in urine and thislowers the blood concentration. For instance, re-absorption ofchlorpropamide from the uriniferous tubules is inhibited by concomitantuse with sodium bicarbonate.

A drug delivery system is defined as technology with which fate of drugmolecules during the course of drug release, absorption, distribution,metabolism, and excretion is precisely controlled in terms of time andspace. Conventional drug delivery systems are used in order toselectively introduce drugs to the site where its effects will bemanifested based on the desired concentration-time pattern and therebyobtain the best clinical results. Examples are targeting technology forincreasing the therapeutic results of anticancer drugs and steroids atthe targeted site while averting adverse reactions outside the targetedsite and controlled release technology for reducing the number ofadministration time of hypotensive agent in I day or for avoidingadverse reactions. The use of the drug delivery system of the presentinvention is in no way intended to alleviate the adverse reactionsinvolved with the drug itself, and it clearly is different from the useof conventional drug delivery systems in that its purpose is to avertundesirable drug interactions between the drug in question andconcomitant drugs.

Of the drug delivery systems, technology for controlling release ofdrugs in particular is used in the present invention. Controlling therelease of drugs is generally classified as (1) controlling the releasetime and (2) controlling the site of release, but there are also caseswhere the site of release is restricted as a result of controlling therelease time and when the release time is delayed as a result ofcontrolling the site of release. Moreover, there are cases in whichthere is merely a difference in which one of these is mainly controlled.

By means of the present invention, drug interaction between a drug andconcomitant drugs is averted by either control by prolonging the drugrelease time by a certain time period or by controlling release of adrug specifically to a certain site in the digestive tract and as aresult, staggering the time at which the drugs will reach the route ofabsorption, distribution, metabolism or excretion over which the drugcompetes with concomitant drugs. Consequently, the drug delivery systemof the present invention includes cases where release of multiple drugsthat are being used concomitantly is controlled, in addition to the casewhere release of only 1 drug is controlled.

Of the drug delivery systems of the present invention, timed-releasecontrol technology and technology for controlling release in the lowerdigestive tract are particularly effective and will be described below.However, the drug delivery system of the present invention is notparticularly limited to these as long as the above-mentioned aversion ofdrug interaction can be achieved.

(1) Timed-Release Control Technology

Timed-release control is technology with which the time until a drugbegins to be released after it has been taken is prolonged for a certaintime. This has the mechanism of initiating release of the drug in thepreparation by extending the time when it comes into contact with thewater content of the digestive tract and in further detail, technologyof the following types have been developed (Gekkan Yakuji, 41(6), 35-38,1999/Igaku no Ayumi, 178(8), 441-444, 1996).

{circle over (1)} Insoluble Membrane Bursting Type

These are preparations where the drug and swelling agent are coated witha membrane that is insoluble in water. The water content penetrates theinsoluble membrane to reach the inside, the inside swells, and theinsoluble membrane at the surface bursts under pressure so that thedrugs inside are exposed to outside liquid. The time until the waterpermeates and the inside swells so that the membrane ruptures determinesthe time when drug release begins. Examples are the TES (time-controlledexplosion system) of Fujisawa Yakuhin Co., Ltd. (Pharm. Tech. Japan, 4,1415-1422, 1988) and the prolonged release tablets of Tanabe Seiyaku(Chem. Pharm. Bull, 11, 3036-3041, 1992), whereby a core tablet made ofswelling disintegrator is compressed into a tablet with a substance withlow water permeability.

{circle over (2)} Cap Breakaway-Type

This is an insoluble capsule filled with drug having a stopper made froma hydrophilic polymer. When water swells the hydrophilic plug and thecap can no longer remain in the opening in the capsule and flips off,the drug inside the capsule comes into contact with outside liquid andis released. The time until the cap flips off determines the time forwhich release of the drug is prolonged. The Pulsincap of Scherer DDS(Pharm. J., 247, 138, 1991), etc., are given.

{circle over (3)} Membrane Permeation Increasing-Type

The preparation is drug and organic acid inside a resin layer comprisingcationic groups. The water content penetrates the resin layer, theorganic acid inside is dissolved, and the acid and cationic groups ofthe resin interact, resulting in an increase in penetrability of theresin and release of the drug. The granules of Tanabe Seiyaku (Maku 19,392-399, 1994) comprising Eudragit RS as the outer layer and organicacid and drug as the inner layer, etc., are given.

{circle over (4)} Hydrogel Layer Dissolving-Type

This is a preparation of drug encapsulated by hydrophilic polymer. Thewater content soaks into the hydrophilic polymer, the polymer gel isgradually dissolved, and the drug inside comes into contact with outsideliquid and is released. The gel shape and gel dissolution determine thetime for which release of the drug will be prolonged. The chronotropicDDS coated with a hydroxypropyl methyl cellulose layer of MilanoUniversity (Eur. J. Pharm. Biopharm, 40, 246-250, 1994) and tablets ofKumamoto University (Chem. Pharm. Bull., 43, 311-314, 1995) wherebyhydroxyethyl cellulose is compressed into the core tablet containingdrug are given as examples.

Furthermore, the applicant developed as an improved form a tablet with acore, which is obtained by compression molding a hydrophilic base and ahydrogel-forming polymer substance together with a core tabletcontaining drug. This preparation can be used as a drug delivery systemfor averting undesirable interaction between multiple drugs metabolizedby the drug-metabolizing enzyme CYP3A4. This preparation preferably is acombination of a freely erodible filler mixed in the core tabletcontaining drug in order to completely dissolve or suspend the drugbefore drug release begins. (see, U.S. patent application Ser. No.______, filed on even date herewith bearing Attorney Docket No.019941-000510, incorporated herein by reference in its entirety for allpurposes). Malic acid, citric acid, polyethylene glycol, sucrose, etc.,are given as examples of the freely erodible filler. A base that has asolubility of no more than 4 ml as the volume of water needed todissolve 1 g of the base is preferred as the hydrophilic base, andwater-soluble polymers such as polyethylene glycol, polyvinylpyrrolidone, etc., sugar alcohols, such as D-sorbitol, xylitol, etc.,saccharides, such as sucrose, maltose, lactulose, D-fructose, dextran,glucose, etc., surfactants, such as polyoxyethylene hydrogenated castoroil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitanhigher fatty acid esters, etc., salts, such as sodium chloride,magnesium chloride, etc., organic acids, such as citric acid, tartaricacid, etc., amino acids, such as glycine, β-alanine, lysinehydrochloride, etc., aminosaccharides, such as meglumine, etc., aregiven as examples. Polyethylene oxide, hydroxypropylmethyl cellulose,carboxymethyl cellulose sodium, hydroxyethyl cellulose, carboxyvinylpolymer, etc., are given as the hydrogel-forming polymer, and those witha high viscosity at the time of gelling or with a high viscosity-averagemolecular weight are preferred.

(2) Technology for Controlling Release in the Lower Digestive Tract

Controlling release in the lower digestive tract is technology forcontrolling initial release of the drug until the preparation hasreached the lower digestive tract, such as the ileum and/or colon, etc.,after being taken. It has the mechanism of releasing the drug in theenvironment of the lower digestive tract.

The ileum and colon have more bacteria than the stomach or upper smallintestine and therefore, by coating the drug with a polymer that isdecomposed by bacterial enzymes, the drug is not released in the stomachor upper small intestines. The polymer at the preparation surface isdecomposed and dissolved and the drug is released after reaching theileum and/or colon. Systems whereby azo aromatic polymers are decomposedby the azo reductase of intestinal flora of the University of Ohio(Science 233, 1081, 1986) and the University of Utah (PharmaceuticalResearch, 9(12), 1540-1545, 1992), systems whereby polysaccharides aredecomposed by the β-galactosidase of intestinal flora of FreiburgUniversity (Pharmaceutical Research 10(10), S218, 1993), and systems ofdecomposition by chitosanase using chitosan of Teikoku Seikayu (JapanesePatent No. Hei 4(1992)-217924) are given. A system that uses alectin-type substance present in the large intestines of the Universityof Utah (Proc. Int. Symp. Control. Rel. Bioact. Mat., 17, 130-131, 1990)is also reported.

Furthermore, there is also the system of the applicants (InternationalDisclosure No. 95/28963) whereby organic acid is generated usingintestinal bacteria and as a result, the film covering the drug isdissolved by said organic acid without affecting pH of the nearby cecumand the drug is specifically released to a site in the colon. Inconcrete terms, it is a system for specific release of drug in the colonof the digestive tract consisting of drug that is coated with a polymerthat is dissolved by an organic acid and a saccharide that quicklygenerates an organic acid as a result of reaction with intestinal florain the lower digestive tract.

The drug preparation for averting drug interaction of the presentinvention can be prepared by conventional methods as an oral solidpreparation, an oral liquid preparation, or an injection using theabove-mentioned timed-release technology and/or technology forcontrolling the site of release and an organic or inorganic carriers,filler, and other additives appropriate for oral or non-oraladministration. The drug preparation of the present invention ispreferably an oral drug preparation.

A system for averting drug interaction that uses the drug deliverysystem of the present invention will now be explained based on the typeof drug interaction.

(a) System for Averting Interaction in Terms of Drug Metabolism

In general, when multiple drugs that are metabolized by adrug-metabolizing enzyme of the same molecular species compete for ametabolizing enzyme in the liver, metabolism of the drug that hasinferior affinity for the metabolizing enzyme is inhibited andinteraction in the form of a rise in the blood concentration andprolonged blood half life is seen. In addition, when a drug that ismetabolized by a certain drug-metabolizing enzyme and a drug thatinterferes with the same metabolizing enzyme are both present in theliver, metabolism is inhibited and interaction in the form of a rise inthe blood concentration and prolonged blood half life is seen.Consequently, competition with concomitant drugs over adrug-metabolizing enzyme can be averted by controlling the release timeso that a drug will reach the drug-metabolizing enzyme in the liver aspecific time after a concomitant drug has been absorbed. Moreover,competition over a drug-metabolizing enzyme can be averted by releasinga drug specifically in the lower digestive tract and thereby staggeringthe time when concomitant drugs reach the liver.

In addition, CYP3A4 accounts for more than half of drug metabolism byCYP and as much as 80% of the amount distributed to the liver is alsodistributed to upper small intestines consisting of the duodenum andjejunum. Therefore, when a drug metabolized by CYP3A4 is orallyadministered, it is metabolized at the epithelium of the smallintestines before it is absorbed from the digestive tract. Consequently,competition over CYP3A4 in the upper small intestines can be averted by(1) delaying the drug release time using timed-release controltechnology, which should avert coexistence of at the site of metabolismof concomitant drugs (epithelium of the small intestines and liver) or(2) by releasing the drug in the ileum and colon in which little CYP3A4is distributed using technology for controlling release specifically inthe lower digestive tract.

For instance, inhibition of midazolam metabolism due to competition withconivaptan and the rise in the blood concentration that accompanies thesame can be averted by administration with a timed-release preparationwith which release of the conivaptan in the digestive tract is delayedby as much as 2 hours, as shown in the examples and test examples givenlater.

(b) System for Averting Interaction in Terms of Drug Absorption

Interaction involving absorption of drugs occurs mainly in the digestivetract with oral administration and is the result of an effect onsolubility and permeability of the intestinal epithelium due to a changein gastric pH. In concrete terms, drug interaction can be averted by (1)timed-release control whereby a drug reaches the site of the digestivetract in question once absorption of concomitant drugs from thedigestive tract has been completed or (2) by technology for controllingthe site of release site whereby the site in the digestive tract atwhich concomitant drugs are absorbed is avoided.

For instance, a reduction in the plasma concentration of cefadroxil dueto competition between cefadroxil and cephalexin over a carrier can beaverted by administration with a timed-release preparation with whichrelease of the cephalexin is delayed by as much as 3 hours.

(c) System for Averting Interaction in Terms of Drug Distribution

Interaction involving drug distribution usually occurs with competitionover a protein in the blood. Drug interaction in the blood can beaverted by timed-release control or releasing a drug specifically in thelower digestive tract so that it reaches the blood after the bloodconcentration of concomitant drugs has dropped to a certain point.

For instance, inhibition of binding of acetohexamide with blood proteinsinduced by aspirin and a rise in the free acetohexamide concentration ofthe blood and hypoglycemic symptoms that accompany the same can beaverted by controlling liberation of acetohexamide from blood proteinsas a result of administration of aspirin with a timed-releasepreparation with which release in the digestive tract is delayed by asmuch as 4 hours after oral administration.

(d) System for Averting Interaction in Terms of Drug Excretion

Interaction involving drug excretion often occurs due to competitionover a carrier in the uriniferous tubules. Interaction in theuriniferous tubules can be averted by timed-release control or releaseof a drug specifically to the lower digestive tract so that a drugreaches the kidneys once excretion of concomitant drugs from theuriniferous tubules has been completed for the most part.

For instance, a reduction in renal excretion as a result of inhibitionof secretion of procainamide via the uriniferous tubules induced bycompetition from cimetidine and an increase in the blood concentrationthat accompanies the same can be averted by oral administration with atimed-release preparation with which release of procainamide in thedigestive tract is delayed by as much as 4 hours so that inhibitionattributed to competition over secretion from the uriniferous tubules iscontrolled.

The system for averting drug interaction of the present invention caninclude other technology as long as the in vivo release time and/orrelease site of 1 or multiple drugs is controlled.

EXAMPLES

The present invention is described below in further details usingexamples and test examples, but the present invention is not limited tothese examples, etc.

Conivaptan (which is used in the following examples, etc.) is easilyobtained by or in accordance with the production method described inInternational Kokai Patent N. 95/03305, and Diltiazem, Ketoconazole,Rhodamine 123, Furosemide, Midazolam and Simvastatin are marked.

Example 1 Conivaptan Timed-Release Preparation

1 part by weight conivaptan hydrochloride, 3 parts by weight HPMC2910,and 0.5 parts by weight polysorbate 80 were dissolved in 85.5 parts byweight dichloromethane-methanol mixture (8:2) and a solid dispersion wasprepared by spray drying. Then 6 parts by weight malic acid were addedto 9 parts by weight solid dispersion and mixed with a mortar andpestle. A core of 150 mg/tablet with a diameter of 6.5 mm was obtainedunder a compression force of 500 kg/punch using an oil press. Separatel,62.5 mg polyethylene oxide (Polyox® WSR303) and 187.5 mg Macrogol 6000were mixed with a mortar and pestle as the outer layer. The core wasplaced in the center of the outer layer and compression-coated tabletsof the present invention of 400 mg (20 mg conivaptan)/tablet with adiameter of 9.5 mm were made under a compression force of 1,000 kg/punchusing an oil press.

Example 2 Diltiazem Timed-Release Preparation

50 parts by weight Macrogol 6000 were added to 100 parts by weightDiltiazem(Wako Junyaku Co.,Ltd.) and mixed with a mortar and pestle.Then core tablets of 150 mg/tablet with a diameter of 7.0 mm wereobtained under a compression force of 500 kg/punch using an oil press.125 mg polyethylene oxide (Polyox® WSR303) and 175 mg Macrogol 6000 wereseparately mixed with a mortar and pestle to make the outer layer. Thecore tablet was placed in the center of the outer layer andcompression-coated tablets of the present invention of 400 mg/tabletwith a diameter of 10.0 mm were produced under a compression force of1,000 kg/punch using an oil press.

Example 3 Ketoconazole Timed-Release Preparation

100 parts by weight malic acid were added to 100 parts by weightKetoconazole(Sigma) and mixed with a mortar and pestle. Then core tabletof 200 mg/tablet with a diameter of 8.0 mm were obtained under acompression force of 500 kg/punch using an oil press. 150 mgpolyethylene oxide (Polyox® WSR303) and 180 mg Macrogol 6000 wereseparately mixed with a mortar and pestle to make the outer layer. Thecore tablet was placed in the center of the outer layer andcompression-coated tablets of the present invention of 530 mg/tabletwith a diameter of 11.0 mm were produced under a compression force of1,000 kg/punch using an oil press.

Example 4 Conivaptan Timed-Release Preparation

1 part by weight conivaptan hydrochloride, 3 parts by weight HPMC2910,and 0.5 parts by weight polysorbate 80 were dissolved in 85.5 parts byweight dichloromethane-methanol mixture(8:2) and a solid dispersion wasprepared by spray drying. Then 8 parts by weight malic acid were addedto 9 parts by weight of the solid dispersion and mixed with a mortar andpestle. Core tablets of 170 mg/tablet with a diameter of 8 mm wereobtained under a compression force of 500 kg/punch using an oil press.150 mg polyethylene oxide (Polyox® WSR303) and 180 mg Macrogol 6000 wereseparately mixed with a mortar and pestle to make the outer layer. Thecore tablet was placed in the center of the outer layer andcompression-coated tablets of the present invention of 500 mg (20 mgconivaptan)/tablet with a diameter of 11 mm were produced under acompression force of 1,000 kg/punch using an oil press.

Example 5 Ketoconazole Timed-Release Preparation

50 mg of citric acid were added to 100 mg of Ketoconazole and mixed witha mortar and pestle. Core of tablet with a diameter of 7.0 mm wereobtained using an oil press. At the same time, 150 mg polyethylene oxide(Polyox® WSR303) and 100 mg Macrogol 6000 were mixed with a mortar andpestle as the outer layer. The core tablet was placed in the center ofthe outer layer and compression coated tablets of the present inventionof 400 mg/tablet with a diameter of 10 mm were made under a compressionforce of 1,000 kg/punch using an oil press.

When Ketoconazole and Famotidine are co-administered orally, there is adecrease in solubility of Ketoconazole in line with the increase ofgastric pH, and as a result there is a reduction in absorbability ofKetoconazole. The tablets obtained in the above were prepared foraverting the reduction in the blood concentration of Ketoconazole byco-administration with Famotidine. When the tablet is orallyadministered, it begins to release Ketoconazole after a certain time inthe lower small intestine and colon, and as a result, there is no effecton solubility of Ketoconazole depending on a change in gastric pH.

Example 6 Rhodamine 123 Timed-Release Preparation

Nonpareil(trade name of spherical granules of sucrose, manufactured byFreund)(particle size: 710-840 m, 500 g) is entered and rolled in acentrifugal fluidized granulator(CF-36) EX, manufactured by Freund) anda mixture of Rhodamine 123(300 g) and fumaric acid (500 g) is graduallyadded thereto while spraying a solution of sucrose(240 g) inwater-ethanol(3:1)(720 g), by which the ninpareil is surrounded andcoated with the active substance and organic acid to give Rhodamine123-containing granules. The Rhodamine 123 granules thus prepared(200 g)are entered into a fluidized bed coating machine(Flow Coater Mini,manufactured by Freund) and there is sprayed a coating liquid consistingof Eudragit RS30D (manufactured by Rohm Pharma, Germany)(168 g), talc(25g), triethylcitrate(5 g) in water(234 g) with hot air-blowing of 60.Thereafter, the mixture is heat-treated at 60 to give controlled releaseRhodamine 123-containing granules(280 g).

The obtained preparation was prepared for averting to promotetranslation into the brain of Verapamil(which is administeredconcomitantly) with inhibition of P glycoproteins by Rhodamine 123,because the release of Rhodamine 123 in the digestive tract is delayedby as much as 4 hours after oral administration.

Example 7 Furosemide Colon-Delivery Preparation

200 mg of lactulose were added to 40 mg of Furosemide and mixed with amortar and pestle. Core of tablet with a diameter of 7 mm were obtainedunder a compression force of 250 kg/punch using an oil press. The weightof the core tablet increased 20 mg after coating by ethanol-watersolution (64:24(weight)) of Eudragit E/hydroxypropylmethylcellose (4: 1)and the weight increased 6.0 mg after coating by water-solution ofhydroxypropylcellose. The weight of the tablet increased 26 mg aftercoating by ethanol-water solution (17:1 (weight)) of EudragitL/talc/triethyl citrate (6:3: 1).

The obtained preparation was prepared for averting delay of reduction ofFurosemide in plasma caused by inhibition of secretion of Furosemidefrom the uriniferous tubules by concomitant drug Probenecid, because thetablets release Furocemide specifically in the colon.

Test Example 1 Dissolution Tests

Dissolution tests were conducted on the preparation in Example 1. Thetests were conducted by the Second Dissolution Testing Method (PaddleMethod) of the Pharmacopoeia of Japan (paddle rotation: 200 rpm) using500 ml of 1 st fluid of the Disintegration Testing Method of thePharmacopoeia of Japan as the dissolution medium. Sampling was performedeach hour and the conivaptan in the sampled solution was determined bythe UV method.

(Results)

The results of the dissolution test are shown in FIG. 1. As is clearfrom the figure, it was confirmed that release of conivaptan startedapproximately 4 hours later with the timed-release preparation ofExample 1.

Test Example 2

The following experiments were conducted using midazolam, which ismetabolized CYP3A4, as a concomitant drug of conivaptan hydrochloride.

(Preparation of Sample Solution)

(1) Aqueous solution for oral administration containing midazolam: Afterpreparing commercial midazolam injectable liquid (brand name: Dormicum®injection) to a concentration of 0.2 mg/ml with aqueous hydrochloricacid solution (pH of 3), HPMC2910 was added at 3-times the amount ofmidazolam to obtain a liquid for oral administration.

(2) Aqueous solution for oral administration containing conivaptan:Conivaptan hydrochloride was dissolved to a concentration of 0.5 mg/mlwith an aqueous hydrochloric acid solution (pH of 3) to obtain a liquidfor oral administration.

(Experiment 1)

Male beagle dogs (n=6) that had been fasted for approximately 20 hourswere orally administered the aqueous solution for oral administrationcontaining midazolam using a catheter for oral administration (4mg/dog). After administration, blood was collected from the veins of thefront legs and the plasma concentration of midazolam was determined bythe HPLC/UV method over time.

(Experiment 2)

Male beagle dogs (n=6) that had been fasted for approximately 20 hourswere orally administered the aqueous solution for oral administrationcontaining conivaptan (10 mg/dog). Thirty minutes after administrationthe aqueous solution for oral administration containing midazolam wasorally administered using a catheter for oral administration (4 mg/dog).After midazolam administration, blood was collected from the veins ofthe front legs and the plasma concentration of midazolam was determinedby the HPLC/UV method over time.

(Experiment 3)

Male beagle dogs (n=6) that had been fasted for approximately 20 hourswere orally administered the timed-release preparation of conivaptan ofExample 1 (20 mg/dog) with 30 ml of water. Thirty minutes afteradministration an aqueous solution for oral administration containingmidazolam (4 mg/dog) was orally administered using a catheter for oraladministration. After midazolam administration, blood was collected fromthe veins of the front legs and the plasma concentration of midazolamwas determined by the HPLC/UV method over time.

(Results)

The results are shown in the following table. TABLE 1 AUC of midazolamplasma concentration AUC (ng · h/ml) Experiment 1 (midazolam singularadministration) 9.0 ± 6.0 Experiment 2 (midazolam singularadministration + 21.2 ± 8.5* aqueous conivaptan solution) Experiment 3(midazolam singular administration + 10.9 ± 7.3  conivaptantimed-release preparation)*p < 0.05 (to Experiment 1)

As is clear from the results from Experiment 1 and Experiment 2, whenthe aqueous solution for oral administration containing conivaptan wasconcomitantly used by oral administration before oral administration ofmidazolam, significant changes were seen in that there was significantelevation of the midazolam blood concentration and the area underconcentration(AUC) curve increased by at least 2-fold, etc., whencompared to singular oral administration of midazolam(Table 1). Thereason for this apparently is conivaptan, which has the same route ofmetabolism by CYP3A4 inhibits metabolism of midazolam in the smallintestines and as a result, there is an increase in the midazolam bloodconcentration and the AUC.

On the other hand, as is clear from the results of Experiment 1 andExperiment 3, when the preparation of Example 1 was concomitantly usedby oral administration before oral administration of the midazolam, themidazolam blood concentration and AUC showed almost the same results aswith midazolam singular administration (Table 1). From this finding itappears that by means of the preparation of the present invention,metabolism of the midazolam by CYP3A4 in the small intestine is notinhibited by conivaptan because conivaptan is released after themidazolam has been metabolized by CYP3A4 in the upper small intestineand as a result, there is no effect on the metabolism bloodconcentration or AUC. Moreover, it was confirmed that the bloodconcentration of conivaptan was enough to provide pharmacologically thetherapeutic or prophylactic effect of conivaptan once the midazolam hadcleared from the blood.

Test Example 3

The following experiments were performed using Diltiazem, which inhibitsmetabolism by CYP3A4, and Midazolam, which is metabolized by CYP3A4.

(Preparation of Sample Solution)

(1) Aqueous solution for oral administration containing midazolam: Afterpreparing commercial midazolam injectable liquid (brand name: Dormicum®injection) to a concentration of 0.2 mg/ml with aqueous hydrochloricacid solution (pH of 3), HPMC2910 was added at 3-times the amount ofmidazolam to obtain a liquid for oral administration.

(2) Aqueous solution for oral administration containing diltiazem:Diltiazem was dissolved to a concentration of 20 mg/ml to obtain aliquid for oral administration.

(Experiment 4)

The aqueous solution for oral administration containing midazolam wasorally administered (4 mg/dog) using a catheter for oral administrationto a male beagle dogs (n=3) that had been fasted for approximately 20hours. After administration, blood was collected from the veins of thefront limbs of the dogs and the midazolam concentration of the plasmawas determined by the HPLC/UV method.

(Experiment 5)

The aqueous solution for oral administration containing diltiazem wasorally administered (200 mg/dog) using a catheter for oraladministration, while at the same time, the aqueous solution for oraladministration of midazolam was orally administered (4 mg/dog) using acatheter for oral administration to male beagle dogs(n=3) that had beenfasted for approximately 20 hours. After administration, blood wascollected from the veins of the front limbs of the dogs and themidazolam concentration of the plasma was determined by the HPLC/UVmethod.

(Experiment 6)

The pharmaceutical preparation of Example 2 was orally administered (200mg/dog) with 30 ml of water using a catheter for oral administration,while at the same time, the aqueous solution for oral administration ofmidazolam was orally administered (4 mg/dog) using a catheter for oraladministration to male beagle dogs(n=3) that had been fasted forapproximately 20 hours. After administration, blood was collected fromthe veins of the front limbs of the dogs and the midazolam concentrationof the plasma was determined by the HPLC/UV method.

(Results)

The results are shown in the following table. TABLE 2 Mean AUC ofmidazolam plasma concentration AUC (ng · h/ml) Experiment 4 (midazolamsingular administration) 55.0 Experiment 5 (midazolam singularadministration + 162.6 aqueous diltiazem solution) Experiment 6(midazolam singular administration + 48.9 diltiazem timed-releasepreparation)

As is clear from the results from Experiment 4 and Experiment 5, whenthe aqueous solution for oral administration containing diltiazem wasconcomitantly used by oral administration simultaneously with midazolamoral administration, there was a marked rise in the blood concentrationof midazolam and the average area under concentration(AUC) increased byas much as 3-times (Table 2) when compared to midazolam singularadministration. The reason for this apparently that diltiazem inhibitsmetabolism by CYP3A4 and as a result, induces an increase in themidazolam AUC.

On the other hand, as is clear from Experiment 4 and Experiment 6,almost the same results as with midazolam singular administration areseen in terms of the midazolam AUC when the pharmaceutical preparationof Example 2 was concomitantly used by oral administrationsimultaneously with midazolam oral administration (Table 2). Thus, itappears that the pharmaceutical preparation of the present inventiondiltiazem is released after midazolam has been metabolized by CYP3A4 inthe upper small intestine and therefore had no effect on the AUC ofmidazolam.

Test Example 4

The following experiments were conducted using Ketoconazole, whichinhibits metabolism by CYP3A4 and Midazolam, which is metabolized byCYP3A4.

(Preparation of Sample Solution)

(1) Aqueous solution for oral administration containing midazolam: Afterpreparing commercial midazolam injectable liquid (brand name: Dormicum®injection) to a concentration of 0.2 mg/ml with aqueous hydrochloricacid solution (pH of 3), HPMC2910 was added at 3-times the amount ofmidazolam to obtain a liquid for oral administration.

(2) Aqueous solution for oral administration containing ketoconazole:Ketoconazole was dissolved to a concentration of 5 mg/ml to obtain aliquid for oral administration.

(Experiment 7)

The aqueous solution for oral administration containing midazolam wasorally administered(4 mg/dog) using a catheter for oral administrationto male beagle dogs (n=2) that had been fasted for approximately 20hours. After administration, blood was collected from the veins of thefront limbs of the dogs and the midazolam concentration of the plasmawas determined by the HPLC/UV method.

(Experiment 8)

The aqueous solution for oral administration containing ketoconazole wasorally administered(100 mg/dog) using a catheter for oraladministration, while at the same time, the aqueous solution for oraladministration of midazoram was orally administered(4 mg/dog) using acatheter for oral administration to male beagle dogs (n=2) that had beenfasted for approximately 20 hours. After administration, blood wascollected from the veins of the front limbs of the dogs and themidazolam concentration of the plasma was determined by the HPLC/UVmethod.

(Experiment 9)

The pharmaceutical preparation of Example 3 was orally administered(200mg/dog) with 30 ml of water using a catheter for oral administration,while at the same time, the aqueous solution for oral administration ofmidazolam was orally administered (4 mg/dog) using a catheter for oraladministration to male beagle dogs (n=2) that had been fasted forapproximately 20 hours. After administration, blood was collected fromthe veins of the front limbs of the dogs and the midazolam concentrationof the plasma was determined by the HPLC/UV method.

(Results)

The results are shown in the following table. TABLE 3 Mean AUC ofmidazolam plasma concentration AUC (ng · h/ml) Experiment 7 (midazolamsingular administration) 68.7 Experiment 8 (midazolam singularadministration + 245.5 aqueous ketoconazole solution) Experiment 9(midazolam singular administration + 69.5 ketoconazole timed-releasepreparation)

As is clear from the results from Experiment 7 and Experiment 8, whenthe aqueous solution for oral administration containing ketoconazole wasconcomitantly used by oral administration before midazolam oraladministration, there was a marked rise in the blood concentration ofmidazolam and the average area under concentration (AUC) increased by asmuch as 4-times (Table 3) when compared to midazolam singular oraladministration. The reason for this is apparently that ketoconazoleinhibits metabolism by CYP3A4 and as a result, induces an increase inthe midazolam AUC.

On the other hand, as is clear from the results of Experiment 7 andExperiment 9, when the pharmaceutical preparation of Example 3 wasconcomitantly used by oral administration simultaneously with midazolamoral concentration, the midazolam AUC showed approximately the sameresult as with midazolam singular administration (Table 3). Thus, itappears that the pharmaceutical preparation of the present invention,ketoconazole is released after the midazolam has been metabolized byCYP3A4 in the upper small intestine and therefore had no effect on theAUC of midazolam.

Test Example 5

The following experiments were conducted using Conivaptan which impairsmetabolism by CYP3A4 and Simvastatin which is metabolized by CYP3A4.

(Preparation of Sample Solution)

(1) Aqueous solution for oral administration containing conivaptan:PEG200 5 mM, phosphatidic acid and conivaptan hydrochloride was mixed atthe rate of 1:1:8 and prepared to a concentration of 1.67 mg/ml toobtain a liquid for oral administration.

(2) Preparation for oral administration containing simvastatin:Commercial Lipovas tablet (Banyu seiyaku) was used.

(Experiment 10)

Simvastatin pharmaceutical preparation for oral administration wasorally administered (25 mg/monkey) to male cynomologous monkeys(n=6)that had been fasted for approximately 12 hours on Test Day 1. Blood wascollected from the femoral vein over time following administration andthe simvastatin concentration of plasma was determined by the LC/MS/MSmethod. An aqueous solution for oral administration containingconivaptan was orally administered (5 mg/monkey) using a nasogastrictube to male cynomologous monkeys(n=6) that had been fasted forapproximately 12 hours or longer each morning from Test Day 2 up to TestDay 6. Simvastatin pharmaceutical preparation for oral administrationwas orally administered (25 mg/monkey) simultaneously with oraladministration of the aqueous solution for oral administrationcontaining conivaptan on Test Day 6. Blood was collected from thefemoral vein over time following administration and the simvastatinconcentration of plasma was determined by the HPLC/UV method.

(Experiment 11)

Simvastatin pharmaceutical preparation for oral administration wasorally administered (25 mg/monkey) to male cynomologous monkeys(n=6)that had been fasted for approximately 12 hours on Test Day 1. Blood wascollected from the femoral vein over time once administration wascompleted and the simvastatin concentration of plasma was determined bythe LC/MS/MS method. The pharmaceutical preparation of Example 4 wasorally administered (20 mg/monkey) to male cynomologous monkeys(n=6)that had been fasted for approximately 12 hours or longer each morningfrom Test Day 2 up to Test Day 6. On Test Day 6, simvastatinpharmaceutical preparation for oral administration was orallyadministered (25 mg/monkey) simultaneously with oral administration ofthe pharmaceutical preparation of Example 4. Blood was collected fromthe femoral vein over time once administration was completed and thesimvastatin concentration of plasma was determined by the HPLC/UVmethod.

(Results)

The results are shown in the following table. TABLE 4 Mean AUC ofsimvastatin plasma concentration rate of AUC AUC Test Day 1/ (ng · h/ml)Test Day 6 Experiment Average Average 10 conivaptan singleadministration (Test 62.7 X24.1 Day 1) aqueous conivaptan solution 806.5(54.1-5.8) co-administration (Test Day 6) 11 conivaptan singleadministration (Test 65.2 X4.1 Day 1) preparation of Example 4 324.3(7.4-0.2) co-administration (Test Day 6)

As is clear from the results of Experiment 10 and Experiment 11, therewere marked changes when simvastatin pharmaceutical preparation for oraladministration was concomitantly used by oral administrationsimultaneously after continuous administration of the aqueous solutionfor oral administration of conivaptan in that the simvastatinconcentration in blood rose markedly and the AUC was approximately24-times or more that of singular administration, etc., when compared tosimvastatin singular oral administration (Table 4). The reason for thisis apparently that conivaptan impairs metabolism by CYP3A4 and as aresult, induces an increase in the simvastatin AUC.

On the other hand, as is clear from the results of Experiment 10 andExperiment 11, when the pharmaceutical preparation of Example 4 wasconcomitantly used by oral administration simultaneously withsimvastatin pharmaceutical preparation for oral administration afterbeing continuously administered, the simvastatin AUC was 4-times higherwhen compared to simvastatin singular administration and was very lowwhen compared to concomitant use with the aqueous solution for oraladministration of conivaptan(Table 3). Thus, it appears that thepharmaceutical preparation of the present invention, conivaptanhydrochloride is released after simvastatin has been metabolized byCYP3A4 in the upper small intestine and therefore, a rise in thesimvastatin AUC can be controlled.

Based on the above-mentioned, it was confirmed that the undesirableeffects on the blood concentration of concomitant drug(s) by a drug whenthe drug and the concomitant drug(s) are metabolized by thedrug-metabolizing enzyme CYP3A4, can be averted with the drug deliverysystem that uses timed-release control of the present invention.

INDUSTRIAL APPLICABILITY

Undesirable pharmacokinetic drug interaction that occurs withconcomitant use of multiple drugs can be averted using the system foraverting drug interaction of the present invention. Consequently, noveltreatment by a combination of drugs that could not be concomitantly usedin the past is possible. Furthermore, drug products can be developed andnovel drug products can be presented from drugs that were impossible todevelop in the past because of drug interaction when used concomitantlywith other drugs, regardless of their excellent pharmacological effectsand lack of problems with adverse reactions.

In addition, it is possible to avert undesirable pharmacokinetic adversereactions when a drug has been taken with a specific food with thesystem for averting drug interaction of the present invention.Consequently, patient compliance will be improved because theprecautions for use explained to the patient by a pharmacist will bereduced.

1. A system for averting undesirable pharmacokinetic drug interactionbetween a drug and concomitant drug(s), which comprises controlling thein vivo release time and/or release site of the drug and/or theconcomitant drug(s).
 2. A system for averting undesirable druginteraction between a drug and concomitant drug(s), both of which usethe same route in terms of in vivo drug absorption, distribution,metabolism or excretion in humans, which comprises controlling the invivo release time and/or release site of the drug and/or the concomitantdrug(s). 3-4. (canceled)
 5. A drug preparation for averting undesirablepharmacokinetic drug interaction between a drug and concomitant drug(s),which comprises controlling the in vivo release time and/or release siteof the said drug.
 6. A drug preparation for averting undesirable druginteraction between a drug and concomitant drug(s), both of which usethe same route in terms of in vivo drug absorption, distribution,metabolism or excretion in humans, which comprises controlling the invivo release time and/or release site of the said drug. 7-9. (canceled)10. A method for averting undesirable pharmacokinetic drug interactionbetween a drug and concomitant drug(s), comprising administering topatients a drug preparation with which the in vivo release time and/orrelease site of the said drug is controlled.
 11. A method for avertingundesirable drug-interaction between a drug and concomitant drug, bothof which use the same route in terms of in vivo drug absorption,distribution, metabolism or excretion in humans, comprisingadministering to patients a drug preparation with which the in vivorelease time and/or release site of the said drug is controllable.12-14. (canceled)
 15. A system for averting undesirable pharmacokineticinteraction between a drug and food(s), which comprises controlling thein vivo release time and/or release site of the drug.